Project Summary This competitive revision of our currently funded clinical trial (AG057552, Exercise for Brain Health with Increased Genetic Risk for Alzheimer's Disease) aims to elucidate the vascular mechanisms whereby exercise training protects brain structure and brain function and improves cognition, of which very little is known. We will focus on cognitively intact older adults who carry the apolipoprotein-E epsilon4 (APOE-?4) allele, a candidate gene for late-onset Alzheimer's disease (AD)1, as well as vascular disease2. There is evidence that compromised cerebral perfusion is associated with cognitive decline and progression along the AD continuum. We have recently shown that 12 weeks of exercise training increased CBF in the anterior cingulate cortex in healthy older adults. Moreover, recent studies have shown that AD patients have lower levels of CACs, which may be leading to endothelial dysfunction. It is unknown, however, if CAC levels are lower in cognitively intact APOE-?4 allele carriers, or if exercise may bolster vascular function through enhanced CAC function. Understanding the mechanisms underlying perfusion deficits that may precede/contribute to cognitive impairments is an important next step in understanding the progression and prevention of AD. Our novel approach with this revision is to determine is whether exercise protects the neural networks of cognitively healthy APOE-?4 allele carriers by bolstering CACs and promoting responsive endothelial function. Our primary aims for the current revision application build on our preliminary data and published work showing that exercise training in older adults: 1) increases circulating angiogenic cells (CACs) and endothelial progenitor cells (EPCs) that promote vessel growth and capillarization and protect cardiometabolic health; and 2) improves vascular function in peripheral arteries and carotid artery. The key unanswered questions we will address are: 1) do the exercise training-induced effects on vascular function in older adults differ among cognitively intact APOE-?4 allele carriers and non-carriers; and 2) are the exercise-induced effects on vascular function in older adults related to changes in MRI indices of brain function, brain structure, and/or changes in cognition? The hub of our single site parent study is the University of Maryland College Park, where we partner with local retirement communities and fitness centers. This competitive revision application leverages two recent hires by the Department of Kinesiology, Dr. Steven Prior and Dr. Sushant Ranadive, both of whom are experts in the fields exercise physiology and human vascular function. Dr. Prior's work focuses on identifying cellular mechanisms of vascular health in older adults induced by exercise and physical activity, including factors that promote angiogenesis and new capillary growth in muscle. Dr. Ranadive is an expert in studying vascular function in older adults, including neurovascular control mechanisms that promote optimal vascular reactivity. Our team is well positioned and highly qualified to investigate if the association between changes in vascular dysfunction and improved cognition and cerebral blood flow are mediated by changes in pro-angiogenic cells after exercise training.